The pain pathway begins in the periphery with nociceptors that innervate skin, muscle, tendon or bone targets. Activated or sensitized nociceptors transmit noxious information to the spinal dorsal horn where spinal neurons then transmit information to rostral centers in the thalamus, reticular formation and midbrain. Other neurons carry the information to the somatosensory cortex where pain is interpreted. Nociceptive information transmitted through the spinal cord is heavily modulated by central neurons whose axons descend from the midbrain and other rostral areas to the spinal cord, and these descending pathways can be either inhibitory or facilitory.
Neurons contain a variety of voltage-gated ion channels. The voltage-gated K+ and Na+ channels regulate the excitability of neuronal cells and play a crucial role in setting the perceptual threshold of pain. The ability to modulate the activity of K+ or Na+ ion channels in neuronal cells is important for regulating the transmission of pain signals.
Epoxyeicosatrienoic acids (EETs) are produced from arachidonic acid via cytochrome P450 (CYP) epoxygenases. EETs regulate inflammation, angiogenesis, cellular proliferation, ion transport and steroidogenesis. In many issues, EET levels are regulated, inter alia, through their metabolism to vic-diols (vic-dihydroxyeicosatrienoic acids; DiHETrE) via the enzyme soluble epoxide hydrolase (EPHX2).
While some types of pain are effectively managed with opioids such as morphine or non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin or ibuprofen, opioids and NSAIDS both have numerous undesirable side effects. For instance, opioids frequently cause dependence and withdrawal problems in users. The use of opioids in the management of pain is further limited due to impairment of Na+/K+-ATPase activity after opiate treatment, a possible mechanism of tolerance/addiction. Similarly NSAIDS can cause hypertension, ulcer perforation, upper gastrointestinal bleeding and even death in severe cases.
Acetaminophen is one of the most widely used drugs in the world for treatment of pain and fever; probably the most commonly prescribed medicine in children. Over 600 products contain acetaminophen including OTC pain, cold and flu remedies and prescription medications like Vicodin. It has a unique position among analgesic drugs. Unlike NSAIDs, it is considered an ineffective anti-inflammatory, but does not produce gastrointestinal damage or untoward cardio-renal effects; unlike opiates, it is ineffective in pain arising from smooth muscle spasm, but has no depressant effect on respiration. The acetaminophen metabolite that produces analgesia is AM404—now known to provide analgesia through CB1 and TRPV1 receptors. FIG. 1 illustrates the metabolism of acetaminophen to AM404 and, in addition, the less desirable molecule NAPQI. Unfortunately acetaminophen is toxic in high doses and is responsible for the majority of the acute liver failure cases in the United States. NAPQI is the molecule largely believed to be responsible for liver failure.
Accordingly, a need exists for improved analgesic treatment that avoids the above-mentioned side effects but provides an effective and safe treatment for pain.